Extrachromosomal DNA-driven oncogene spatial heterogeneity and evolution in glioblastoma
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Imran Noorani Magnus Haughey Jens Luebeck Andrew Rowan Eva Gronroos Francesco Terenzi Ivy Tsz-Lo Wong Davide Pradella Marta Lisi Jeanette Kittel Natasha Sharma Chris Bailey Clare Weeden Donald Bell Eric Joo Vittorio Barbè Matthew G Jones King L Hung Emma Nye Mary Green Lucy Meader Emma J Norton Mark Fabian Nnennaya Kanu Mariam Jamal-Hanjani Thomas Santarius Andrea Ventura James AR Nicoll Delphine Boche Howard Y Chang Vineet Bafna Weini Huang Paul S Mischel Charles Swanton Benjamin Werner
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Abstract
UNLABELLED: Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA. We observe oncogene-specific patterns of ecDNA spatial heterogeneity, emerging from random ecDNA segregation and differing fitness advantages. Unlike PDGFRA-ecDNAs, EGFR-ecDNAs often accumulate prior to clonal expansions, conferring strong fitness advantages and reaching high abundances. In corroboration, we observe pretumor ecDNA accumulation in vivo in genetically engineered mouse neural stem cells. Variant and wild-type EGFR-ecDNAs often coexist in GBM. Those variant EGFR-ecDNAs, most commonly EGFRvIII-ecDNA, always derive from preexisting wild-type EGFR-ecDNAs, occur early, and reach high abundance. Our results suggest that the ecDNA oncogenic makeup determines unique evolutionary trajectories. New concepts such as ecDNA clonality and heteroplasmy require a refined evolutionary interpretation of genomic data in a large subset of GBMs. SIGNIFICANCE: We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene-specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs. See related article by Korsah et al., p. XX.
Journal details
Journal
Cancer Discovery
Volume
15
Issue number
10
Pages
2078-2095
Available online
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10.1158/2159-8290.CD-24-1555
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Europe PubMed Central
40920091
Pubmed
40920091
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The publication was previously a preprint.
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